FINDER - Fighting dengue virus: an innovative approach for the development of pan-serotype antivirals that act by disrupting the interaction between NS3/NS5 viral proteins

FINDER project aims at developing new therapeutic antiviral small molecules able to inhibit the replication of the four different dengue virus (DENV) sierotypes and other mosquito-borne flavivirus such as Zika virus (ZIKV) and West Nile virus (WNV). Every year, flaviviruses cause worldwide millions of infections and deaths in tropical regions and can also be responsible of epidemic outbreaks in different European countries, including Italy. Currently, there are no drugs available for the treatment of mosquito-borne flavivirus.

The strategy that is applied within FINDER deals with the disruption of the protein-protein interaction between NS3 and NS5 proteins, the unique flaviviral proteins endowed with enzymatic activity. NS3-NS5 interaction is essential for the replication of viral genome and for the viral cycle, as well as is conserved across flavivirus; thus, it represents an attractive, albeit poorly explored, therapeutic target. Within FINDER, we studied NS3-NS5 interaction of different flaviviruses by molecular dynamics simulation methods and then an in silico screening of a million of molecules potentially able to disrupt NS3-NS5 interaction. The hits emerged fromm the screening were then tested by both biochemical and cell-based assays for their ability to inhibit NS3/NS5 interaction and virus replication in infected cells. Two small molecules with pan-flavivirus activity (against all DENV sierotypes, ZIKV, and WNV) acting by a dissociative mechanism agains NS3-NS5 were identified. Currently, these two promising molecules are under preclinical development for the evaluation of their efficacy in a murine model of DENV and ZIKV infection. The results of FINDER project represent an innovative starting platforms for the development of new antiviral drugs with broad spectrum activity.